XYY [HGL]
In the 1960's, several studies identified an increased
frequency of men with the XYY genotype in prison populations. These
observations led to the hypothesis that the extra Y chromosome
caused aggressive and violent behavior. See, e.g., Jacobs,
1965; Hook, 1973. The association between the XYY genotype
and antisocial behavior has been hotly debated. A comprehensive
study in 1976 of males born between 1944 and 1947 in Denmark
found no support for the hypothesis. Witkins et al., Science,
193: 547-555, 1976. Instead, they found that in the general
population XYY men did not differ from genotypically normal XY
men in violent or criminal behavior. However, the found
that XYY men were more likely to be taller than their normal
counterparts. In addition, they scored significantly
and substantially lower on intelligence tests than normal XY
men. Schiavi et al., Arch. Gen. Psychiatry, 41:93-99,
1984.

monoamine oxidase A (MAOA) [HGL] [GE]
MAOA is involved in the metabolism of the monoamine
neurotransmitters dopamine, serotonin, epinephrine, and norepinephrine.
MAO inhibitors are used to treat depression disorders. A
Dutch family was identified with a recessive X-linked condition
characterized by mild mental retardation and aggressive, sometimes
violent, behavior. Four generations of affected males were
identified. The locus of the disorder was mapped to
the p11-21 position on the X-chromosome, coincident with the locus
of an MAOA gene. Consistent with an MAOA gene defect, affected
males displayed a marked disturbance in monoamine metabolism. Brunner
et al., A. J. Hum. Genet., 52:1032-1-39, 1993; Morell, Science,
260:1722-1723, 1993. A line of transgenic mice were created
in which the MAOA gene was deleted. These mice displayed
higher brain concentrations of serotonin and epinephrine. Pups
showed a number of phenotypes associated with the MAO deficiency,
including trembling, difficulty in righting and fearfulness. Adult
males showed enhanced aggression. Cases et al., Science,
268:1763-1766, 1995. A study of 110 men showed an association
between polymorphisms in the MAOA gene and aggressiveness, impulse
control, and cental nervous system responsiveness. Two types of
polymorphisms were studied: a 30-base pair VNTR (variable
nucleotide tandem repeat) in the promoter region and a dinucleotide
repeat in intron 2. Manuck et al., Psychiatry Res., 95:9-23,
2000.

nitric oxide synthase, endothelial isoform (eNOS) [GE]
Mice with targeted deletions of the endothelial
isoform of nitric oxide synthase (eNOS) were less aggressive compared
with wild-type animals as measured by the resident-intruder model
of aggression. Mice homozygous-deficient for the eNOS gene
were hypertensive, as well, but such hypertension did not appear
to be responsible for the diminished aggression since reduction
of blood pressure with drugs did not alter the prevalence of aggression. J.
Neurosci. (Online), 19:RC30, 1999.

nitric oxide syntheses, neuronal isoform (nNOS) [GE]
Nitric oxide acts as a neural messenger in both
the central and peripheral nervous systems. Male mice in
which the neuronal isoform of nNOS has been functionally disrupted
show inappropriate sexual behavior and exhibit an increase in the
number and duration of aggressive encounters compared to wild-type,
control, animals when tested in a variety of paradigms used to
test rodent aggression. This aggressive behavior has only been
observed in nNOS mutant mice; nNOS deficient female mice, like
female wild-type, exhibit little or no aggression. Studies
showed that reducing systemic testosterone by castration reduced
aggression in both wild-type and mutant nNOS males to equivalent
low levels. Testosterone replacement restored aggression to precastration
levels in both genotypes. These data provide evidence that increased
aggressive behavior of mutant nNOS mice, like aggression in wild-type
mice, is testosterone-dependent. Kriegsfeld et al., Brain Res.,
769(1):66-70, 1997; Demas et al., Mol. Med., 3(9):610-616, 1997;
Nelson et al., Nature, 378(6555):383-386, 1995.

regulator of G-protein signaling-2 (rgs2) [GE]
Regulator of G-protein signaling-2 (rgs2) is
a member of a family of genes which accelerate the GTPase activity
of G-proteins. They contain a conserved RGS domain of about
120 amino acids. rgs2 is up-regulated in the central nervous
system after stimuli which evoke long-term neuronal plasticity. To
investigate its in vivo role, rgs2-deficient mice were generated. The
rgs2 deficieny had no apparent effect on motor responses, exploratory
behavior, spatial learning, or memory. However, mice lacking
the rgs2 gene completely (rgs2-/rgs2-) showed reduced male aggression
when compared to heterozygous (rgs2-/rgs2+) littermates. The
aggressive response of female mice deficient in rgs2 was normal. In
addition to aggression, rgs2-deficient mice showed increased anxiety
as compared to heterozygous littermates (data comparing males and
females in the anxiety test were not presented.) Differences
in the CA1 hippocampal neursons were observed in rgs-deficient
mice as compared to controls. Oliveira-dos-Santos et al.,
Proc. Natl. Acad. Sci., 97:12272-12277, 2000. See, also,
entry under Neuroticism.

serotonin receptor, type 1B (5-HT1B) [GE]
Mice were generated which lack the 5-HT1B receptor.
When confronted with an intruder, isolated mutant mice attacked
the intruder faster and more intensely than wild-type mice, suggesting
an involvement of 5-HT1B receptors in the modulation of aggressive
behavior. These data are consistent with other findings that certain
impulsive aggressive behaviors are associated with deficits in
central serotonin. Ramboz et al., Behav. Brain. Res., 73(1-2):305-312,
1996.

serotonin transporter (5-HTT or SERT) [HGL]
A common 44-base pair polymorphism in the promoter
of the serotonin transporter is associated with affective illness
and anxiety disorders. The polymorphism has been designated
long (L) and short (S), depending on whether the insertion is present
or absent in the promoter region. The S allele is less active
than the L allele. The frequency of the S allele was higher
in type 2 alcoholics than in type 1 alcoholics and healthy controls. Type
2 alcoholics display early onset alcholism associated with antisocial
personality disorder and impulsive, habitually violent behavior. Type
1 alcoholism is late-onset and non-violent. Hallikainen et
al., Mol. Psychiatry, 4:385-388, 1999.

tryptophan hydroxylase (TPH) [HGL]
Tryptophan hydroxylase (TPH) is involved in
the biosynthesis of serotonin. A polymorphism was located
in intron 7 of the TPH gene. A population of men and women
were analyzed for aggression and anger-related traits of personality,
and the presence of the U and L polymorphism of the TPH gene. Individuals
having a U allele of the TPH gene scored significantly higher on
measures of aggression and tendency to experience unprovoked anger. Such
individuals were also more likely to outwardly express anger than
individuals homozygous for the L allele. Manuck et
al., Biol. Psychiatry, 45:603-614, 1999.